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Cellular mechanisms underlying the development of catecholaminergic ventricular tachycardia.

Abstract：

BACKGROUND:Mutations in the ryanodine 2 receptor (RyR2) gene have been identified in patients with catecholaminergic polymorphic ventricular tachycardia. We examined the cellular basis for the ECG features and arrhythmia mechanisms using low-dose caffeine to mimic the defective calcium homeostasis encountered under these conditions. METHODS AND RESULTS:A transmural ECG and action potentials were recorded simultaneously from epicardial, M, and endocardial cells in arterially perfused canine ventricular wedge preparations. Caffeine alone produced no change (10 to 100 micromol/L) or a slight abbreviation (300 micromol/L) of the QT interval and no change in transmural dispersion of repolarization. Isoproterenol (100 nmol/L) alone induced sustained monomorphic ventricular tachycardia (VT) that originated in the epicardium in 3 of 14 wedge preparations. Isoproterenol in the presence of caffeine (100 to 300 micromol/L) induced epicardial VT in 9 of 16 wedge preparations. Delayed afterdepolarization-induced triggered beats that originated in the epicardium were associated with an increased Tpeak-Tend interval and transmural dispersion of repolarization. Bidirectional VT developed in 11 of 16 wedge preparations as a consequence of alternation in the origin of ectopic activity between endocardial, M, and epicardial regions. Single extrastimuli delivered during sustained epicardial VT induced a rapid polymorphic VT/ventricular fibrillation (VF) in 3 of 9 wedges. Spontaneous polymorphic VT was observed in 3 of 16 preparations. Propranolol (1.0 micromol/L) or verapamil (1.0 micromol/L) completely suppressed ectopic activity that arose from the epicardium and prevented induction of polymorphic VT. CONCLUSIONS:Our data suggest delayed afterdepolarization-induced extrasystolic activity serves to trigger catecholamine-induced VT/VF under conditions of defective calcium handling. Epicardial origin of the ectopic beats increases transmural dispersion of repolarization, thus providing the substrate for the development of reentrant tachyarrhythmias that underlie rapid polymorphic VT/VF.

journal_name

Circulation

journal_title

Circulation

authors

Nam GB,Burashnikov A,Antzelevitch C

doi

10.1161/CIRCULATIONAHA.104.479295

subject

Has Abstract

pub_date

2005-05-31 00:00:00

pages

2727-33

issue

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.104.479295

journal_volume

111

pub_type

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Cellular mechanisms underlying the development of catecholaminergic ventricular tachycardia.